A Review of the Role of Anticholinergic Activity in Lewy Body Disease and Delirium

Kitajima, Yuriko; Hori, Koji; Konishi, Kimiko; Tani, Masayuki; Tomioka, Haruaki; Akashi, Norihisa; Hosoi, Misa; Inamoto, Atsuko; Hasegawa, Sayaka; Kikuchi, Nodoka; Takahashi, Akari; Hachisu, Mitsugu

doi:10.1159/000381522

Cited by 16 publications

(21 citation statements)

References 26 publications

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“…Both DLB and PDD show similar morphological fea-αSyn causing additional symptoms that accelerate the disease course [96]. On the other hand, galanin upregulation within the basal forebrain cholinergic system in DLB, similar to that in AD but not in PDD, may represent an intrinsic adaptive response to neurodegeneration of these areas [97].…”

Section: Neuropathological Featuresmentioning

confidence: 99%

Dementia with Lewy Bodies and Parkinson's Disease-Dementia: Current Perspectives

A¹

2018

Int J Neurol Neurother

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Dementia with Lewy bodies (DLB) and Parkinson's disease-dementia (PDD) are two closely related major neurocognitive disorders with Lewy bodies of unknown etiology, showing notable overlap in their clinical presentation, pathological features, biochemistry, and genetic risk factors. According to international consensus, their diagnosis is based on an arbitrary distinction between the time of onset of motor and cognitive symptoms: dementia preceding parkinsonism in DLB, while it develops after onset of parkinsonism in PDD (the one-year rule). Clinically, both syndromes show cognitive impairment with severe deficits in executive function, visuo-spatial processing, fluctuating attention and parkinsonism, with higher prevalence of Alzheimer-type lesions in DLB that may account for earlier onset and severity of cognitive deficits. These are also associated with multiple neurotransmitter deficits indicating that cognitive impairment in Lewy body disesses is multifactorial. Recent intra vitam neuroimaging, clinico-pathological studies and animal models suggest that DLB and PDD represent closely related but different, heterogenic subtypes of an α-synuclein-associated disease spectrum (Lewy body diseases) or parts of a continuum with PDD at the mild end of the spectrum, DLB in the middle, and DLB+AD at the more severe end. In view of the controversies about the nosology of both disorders, continuous effort is necessary to differentiate them more clearly and to clarify the underlying pathogenic mechanisms in order to enable effective mechanistic-based treatment, while, currently, no disease-modifying therapies are available.

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Section: Neuropathological Featuresmentioning

confidence: 99%

Dementia with Lewy Bodies and Parkinson's Disease-Dementia: Current Perspectives

A¹

2018

Int J Neurol Neurother

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“…Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and the small amount of downregulation of ACh. It is plausible to conclude that in depression and LBD AA might appear endogenously [12,13]. In depression, the cholinergic system is burdened secondarily to the underlying depressive pathology.…”

Section: Opinionmentioning

confidence: 99%

Role of Cholinergic System in Neuropsychiatric Disorders

Hori¹

2017

Anat Physiol

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OpinionNeedless to say acetylcholine (ACh) is relared with cognitive function [1]. However, ACh also suppresses inflammatory system [2], therefore, downregulation of ACh not only causes cognitive dysfunction, but also accelerates inflammatory system. This hyperactivity of inflammatory system is related with various neuropsychiatric disorders including Alzheimer's disease (AD) [3] and depression [4].Moreover, we also speculate this hyperactivity of inflammatory system also induces anticholinergic activity (AA) and this AA accelerates amyloid pathology [5]. Based on this speculation, we propose "the hypothesis of endogenous appearance of AA in AD" [6]. That is, when the downregulation of ACh reaches critical level, AA appears endogenously by way of hyperactivation of inflammatory system and accelerates amyloid pathology [5,6]. Because the factors those cause AA and now reported three other than downregulation of ACh, i.e., medication [7], physical illness [8] and mental stress [9]. Therefore, it is natural that when based on the small amount of deterioration of ACh other AA insert is added, AA also appears [10]. In fact, we showed the patient with AD at MCI level whose serum anticholinergic activity might be positive caused by both small amount of down regulation of ACh and mental stress [11]. Moreover, overburden of cholinergic system might also attribute to the appearance of AA because ACh is no more upregulated in order to compensate for AA insert (upregulation of ACh). Therefore there might be a possibility of the appearance of AA in other disease than AD. We also speculate there might be a possibility of the endogenous appearance of AA in depression and Lewy body disease (LBD). Increased activity of the hypothalamic-pituitary-adrenal (HPA) axis and the small amount of downregulation of ACh. It is plausible to conclude that in depression and LBD AA might appear endogenously [12,13]. In depression, the cholinergic system is burdened secondarily to the underlying depressive pathology. During remission, activity of cholinacetyl transferase (ChAT), an enzyme that produces ACh, might be sufficiently upregulated to compensate for the cholinergic burden caused by depressive pathology. However, at the pathological state (depressive state), more upregulation of ACh is not impossible because the ChAT activity is already upregulate. Therefore, in depression there might be a possibility of endogenous appearance of AA [14]. In delirium, we also speculate there might be a possibility of the appearance of AA in delirium. In delirium, increased activity of the HPA axis by exogenous factor, i.e., physical illness, medication or mental stress and the small amount of downregulation of ACh caused by aging or AD, AA also appears.From these considerations we speculate that at least in AD, LBD and depression, the progression of disease might be related with AA at least late sage. Alternatively at late phase of AD, LBD and depression, main pathology might be amyloid pathology. We propose the concept of "anticholinergic spectrum disor...

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“…We consider mental stress and other factors besides ACh downregulation to be capable of inducing SAA, to be so-called “AA inserts.” In this context, because there are other AA inserts besides ACh downregulation [ 9 , 10 ], such as the prescribed medication [ 6 ], physical illness [ 7 ], and mental stress [ 8 ], dual actions of AA inserts can also cause AA when the ACh level does not reach a critical level (i.e., at the stage of mild cognitive impairment or at a mild stage of the disease) [ 24 ]. Based on this case, we speculated that the appearance of AA might cause psychiatric symptoms such as delusions, hallucinations, and diurnal rhythm disturbances in delirium and LBD based on the dual actions of ACh downregulation [ 11 ] (if ACh is not deteriorated or overloaded, the intact ACh system can be upregulated and compensate for another AA insert [ 10 ]) and the effects of another AA insert.…”

Section: Dual Actions Of Anticholinergic Inserts Cause Anticholinementioning

confidence: 99%

“…These processes might also accelerate AD pathologies [ 9 , 10 ]. Moreover, we speculated that, in addition to AD, other neurocognitive disorders such as Lewy body disease (LBD) and delirium are related to AA and that the appearance of AA in LBD is also related to an endogenous factor [ 11 ]. In this article, we rereview our hypotheses surrounding the endogenous appearance of AA in AD [ 9 , 10 ] and LBD [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, we speculated that, in addition to AD, other neurocognitive disorders such as Lewy body disease (LBD) and delirium are related to AA and that the appearance of AA in LBD is also related to an endogenous factor [ 11 ]. In this article, we rereview our hypotheses surrounding the endogenous appearance of AA in AD [ 9 , 10 ] and LBD [ 11 ]. We also theorize that the onset of clinical symptoms in LBD depends on the endogenous appearance of AA in LBD and propose a new concept of “anticholinergic spectrum disorders.”…”

Section: Introductionmentioning

confidence: 99%

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Mini Review: Anticholinergic Activity as a Behavioral Pathology of Lewy Body Disease and Proposal of the Concept of “Anticholinergic Spectrum Disorders”

Hori

Konishi²,

Hosoi

et al. 2016

Parkinson's Disease

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Given the relationship between anticholinergic activity (AA) and Alzheimer's disease (AD), we rereview our hypothesis of the endogenous appearance of AA in AD. Briefly, because acetylcholine (ACh) regulates not only cognitive function but also the inflammatory system, when ACh downregulation reaches a critical level, inflammation increases, triggering the appearance of cytokines with AA. Moreover, based on a case report of a patient with mild AD and slightly deteriorated ACh, we also speculate that AA can appear endogenously in Lewy body disease due to the dual action of the downregulation of ACh and hyperactivity of the hypothalamic-pituitary-adrenal axis. Based on these hypotheses, we consider AA to be a behavioral pathology of Lewy body disease. We also propose the concept of “anticholinergic spectrum disorders,” which encompass a variety of conditions, including AD, Lewy body disease, and delirium. Finally, we suggest the prescription of cholinesterase inhibitors to patients in this spectrum of disorders to abolish AA by upregulating ACh.

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A Review of the Role of Anticholinergic Activity in Lewy Body Disease and Delirium

Cited by 16 publications

References 26 publications

Dementia with Lewy Bodies and Parkinson's Disease-Dementia: Current Perspectives

Dementia with Lewy Bodies and Parkinson's Disease-Dementia: Current Perspectives

Role of Cholinergic System in Neuropsychiatric Disorders

Mini Review: Anticholinergic Activity as a Behavioral Pathology of Lewy Body Disease and Proposal of the Concept of “Anticholinergic Spectrum Disorders”

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